Control and Regulation of Respiration

Respiration is well regulated both at central and peripheral levels in the body. The centre for respiration, or the respira­tory centre, is situated in the medulla oblongata and pons that controls breathing.

7.9.1 Medullary Control

The dorsal respiratory group (DRG) and the ventral respira­tory group (VRG) comprise the medullary control centres of respiration.

Dorsal respiratory group: The major component of the dorsal respiratory group is the nucleus tractus solitarius (NTS). It contains inspiratory or I neurons which form the centre of inspiration. The NTS receives afferent inputs from some regions of VRG neurons, inputs that modulate respiration from peripheral arterial chemoreceptors, upper airway and lungs. The various respiratory inputs are integrated into the NTS. When this centre is stimulated, the inspiratory or I neurons fire and send impulses to the neurons supplying the inspiratory muscles. Contraction of these muscles occurs, which begins the process of inspiration.

Ventral respiratory group: These respiratory neurons are situated in the ventral part of the medulla and are involved in both inspiration and expiration. This area primarily consists of expiratory neurons in addition to some inspira­tory neurons. When the ventral respiratory group of neurons is stimulated, it leads to expiration. The VRG encompasses several adjacent compartments that include the pre-Botzinger complex (preBotC), the Botzinger com­plex (BotC) and retrotrapezoid/parafacial nucleus (RTN/pFG). Whereas the pre-Botzinger complex (preBotC) is a neural network responsible for inspiration during respiratory activity and a central pattern generator with respect to respiration (respiratory rhythm generator), the retrotrapezoid nucleus (RTN) is located on the ventral surface of the brain and contains chemosensitive cells that can detect pH alterations.

7.9.2 Pontine Respiratory Centres

The pneumotaxic and the apneustic centres help set up the breathing rate by influencing the depth of breathing. The pneumotaxic centre inhibits the inspiratory area and thus helps to stop inspiration. The apneustic centre stimulates the inspiratory area, prolonging inspiration (apneusis or deep sigh). But the pneumotaxic centre is dominant over the apneustic centre, so when the pneumotaxic centre is active, the apneustic centre is overridden by it.

The pneumotaxic centre: The pneumotaxic centre is situated in the upper part of the pons and is comprised of the parabrachial and Kolliker-Fuse nuclei. The pneumotaxic centre is responsible for controlling the rate and breathing pattern. This centre limits the inspiration, providing an inspiratory off-switch (IOS) by restricting the firing of action potentials in the phrenic nerve, thereby decreasing the tidal volume. Lesions in this centre are associated with a reduced respiratory rate with an increase in the depth of respiration. It has connections with the DRG of the medulla; hence, when needed, it can send signals to increase the breathing rate.

The apneustic centre: Apneusis, or apneustic breathing, is an abnormal breathing pattern that is characterised by a full inspiration followed by a prolonged pause. This centre in the lower pons promotes prolonged inspiration by con­tinuously stimulating the neurons in the medulla oblongata. The medulla (dorsal group) receives signals from the apneustic centre to prolong the inspiratory off-switch (IOS) signal generated by the pneumotaxic centre. These positive impulses to the inspiratory neurons, in turn, control the intensity of breathing. Impulses from the pulmonary stretch receptors and pneumotaxic centre inhibit the apneustic centre. Thus, the centre, in turn, can also inhibit the pneumotaxic centre.

7.9.3 Other Higher Centres Controlling Respiration

The spontaneous rhythmicity-generated impulse in the med­ullary respiratory centre can be completely overwhelmed (at least temporarily) by influences from the higher brain centres (hypothalamus, limbic system, cortex).

1. Hypothalamus is involved in the respiratory modifications during pleasure, anger and fever.

2. Limbic system is involved in the emotional responses.

3. Cortex controls maximum voluntary ventilation and respiratory modifications during the speech, singing, playing wind instruments and emotional states.

7.9.4 Reflexes and Chemical Control of Respiration

Breathing is modulated by several reflexes emanating from different sites in the body. Some of them are physical reflexes, and others are chemical reflexes.

7.9.4.1 Physical Reflexes

7.9.4.1.1 Herring-BreuerReflex

In 1868, two physiologists, Herring and Breuer, reported that enlargement of the lungs of anaesthetised animals decreases the frequency of inspiratory efforts, whereas collapse has the opposite effect, thus concluding that lung receptors modulate the pattern of breathing. This phenomenon is termed as Herring-Breuer reflex. If it takes place during inspiration, it is called inflation reflex (HBIR), and if it takes place to terminate further expiration, it is called deflation reflex (HBDR). Slow-adapting receptors (SARs) in the lungs and pleural tissues are stimulated by the pulmonary stretch during inspiration-associated inflation to terminate further inspira­tion and overinflation (inspiratory switch off). Similarly, pulmonary stretch extends the period between subsequent breaths, and pulmonary deflation quickens the next inspira­tion. The vagus nerve conveys the afferent impulses to pump cells present in and around the ventrolateral nucleus solitary tract. These cells project to inspiratory neurons in the lateral respiratory column and halt the respiration by releasing inhib­itory neurotransmitters. In other words, it is often considered an inhibitory sensory feedback loop that shapes the respira­tory motor pattern.

This reflex is strongest in neonates, especially at birth, but decreases during the first year of life. It occurs due to an excessively compliant chest wall in newborns that can col­lapse at volumes below functional residual capacity during expiration, thereby activating HBDR.

7.9.4.1.2 JReflex

In 1970, an Indian physiologist, Autar Singh Paintal, first described the J reflex. These receptors are located within alveolar septa and are juxtaposed to the pulmonary capillaries and are hence called juxta-pulmonary capillary receptors or J receptors. Due to their widespread presence in most tissues, they are also known as pulmonary C fibre receptors and are non-myelinated afferent fibres. They are considered irritant receptors, responding to noxious stimuli like chemical irritants or dust. They also react to inflammation or accumu­lation of fluid within the pulmonary interstitium and trigger tachypnoea.

7.9.4.2 Chemical Control of Respiration

The chemical changes controlling respiration are mediated by chemoreceptors, which are sensors that can detect alterations in oxygen, carbon dioxide and pH. They are located either in the brain (central chemoreceptors) or other peripheral areas of the body (peripheral chemoreceptors).

7.9.4.2.1 Central Chemoreceptors

They occur in various parts of the brain, viz. cerebellum, midbrain, hypothalamus and brainstem. Central chemorecep­tion has two major physiological functions: (1) maintenance of a constant, normal arterial PCO₂ and (2) maintenance of a constant pH through the exchange of CO₂ by ventilation to correct the acid-base disturbances. The central chemoreceptors also control a more comprehensive range of physiological processes. The central and peripheral chemoreceptors are CO₂/H⁺ sensitive that can sense the level of CO₂ in arterial blood and alveolar air and provide instant feedback to the brainstem respiratory control system. This PCO₂ value is deter­mined by the ratio of metabolic CO₂ production at tissues and the amount of alveolar ventilation.

Central chemoreceptors monitor brain interstitial fluid (ISF) pH, which is determined by tissue PCO₂ and bicarbon­ate. Three factors determine tissue PCO₂: the arterial PCO₂, the rate of CO₂ production by medullary tissue and the cerebral or medullary blood flow (CBF). In this view, central chemoreceptors may detect arterial PCO₂ and serve as a chemical feedback loop in the control of breathing and changes in tissue pH that result from acid-base disorders that arise either in the periphery or centrally.

Increased PCO₂ vasodilates cerebral vessels, and CBF increases; decreased PCO₂ vasoconstricts cerebral vessels, and CBF decreases. Increased arterial PCO₂ increases ISF H⁺, stimulates central chemoreceptors and vasodilates cere­bral vessels. The resultant increase in CBF decreases tissue PCO₂ widening the arterial tissue PCO₂ difference and minimising the initial stimulus intensity at the chemoreceptors. Conversely, decreased arterial PCO₂ decreases ISF H⁺, inhibits central chemoreceptors and vasoconstricts cerebral vessels. The resultant reduction in CBF increases tissue PCO₂ diminishing the arterial tissue PCO₂ difference and minimising the degree of central che­moreceptor inhibition. Thus, the responses of CBF to changes in PCO₂ serve both to maintain ISF pH relatively constant and to modulate the central chemoreceptor response to a level appropriate for the ISF pH stimulus intensity.

7.9.4.2.2 Peripheral Chemoreceptors

The peripheral chemoreceptor, especially the carotid body, was first anatomically described in 1762 by Albrecht von Haller. But only in 1900 was its physiological function described by Kohn.

The carotid bodies are located bilaterally in the neck, at the anterior end of the left and right common carotid arteries. Similarly, there are other chemoreceptor structures called aortic bodies in the aortic arch region, which are structurally similar to the carotid bodies. The glossopharyngeal nerve and the vagus nerve carry the chemoreceptor input to the brainstem, making synapses with neurons in the DRG.

The carotid body is comprised of type I and type II cells. Type I are the most abundant cells and are referred to as “glomus”, “chief”, “epithelioid” or simply “chemoreceptor” cells. Type II cells are termed “sustentacular or sheath” cells or “pericyte”. The organisation of these cell types within the carotid body is non-uniform, with type II cells forming 20% of the total population being closely connected with type I cells which form small groups with 3-5 cells. The carotid body primarily responds to hypoxia and responds to many other respiratory and nonrespiratory stimuli, including CO₂, pH, glucose, proinflammatory cytokines, circulating hormones, K⁺, osmolarity and temperature. These observations raise the question of whether the carotid body is a “polymodal” sensory receptor or whether these stimuli modify some elements of the O₂ transduction pathway. Future studies addressing the carotid body response to these “other” stimuli may prove to be as relevant for human health as the response to hypoxia.

In response to falls in arterial PO₂, the glomus cells depolarise due to a decrease in K⁺ efflux and ensuing activa­tion of the voltage-gated Ca²⁺ channels. Carotid body produces a characteristically non-linear, graded chemo affer­ent discharge in the carotid sinus nerve. The in vivo increase in discharge frequency gradually reduces below P_aO₂ of 20-30 mmHg and may even fall sometimes, often with the failure to maintain adequate systemic blood pressure.

The carotid body helps to maintain normal level of venti­lation in sleep. During sleep, the apnoea that occurs within seconds of transient hyperventilation has been attributed to hypocapnia sensed in the carotid body.

Central and peripheral chemoreceptors are interdependent for functional activity rather than being separate entities. Under its ability to maintain neuronal excitability, the tonic drive influences the ventilation and regular respiratory rhythm in adults. Drive can arise from many sources, e.g. the activity of the reticular formation, excitatory input from afferents involved in respiratory control and inputs related to CO₂ sensed by central (and peripheral) chemoreceptors.

Based on their location in the body, two types of chemoreceptors have been recognised: central and peripheral. The differences between the central and peripheral chemoreceptors are outlined in Table 7.4.

7.9.5 Regulation of Respiration During Exercise and at High Altitudes

The brain simultaneously sends motor impulses to the muscles during exercise as well as excitatory impulses to activate the respiratory centre in the brainstem.

When one individual begins to exercise, the first response is the increase in ventilation before any changes in blood chemicals occur. It is presumed that neurogenic signals trans­mitted directly into the brainstem respiratory centre produce most of the increase in respiration, which also reaches the muscles and results in muscle contraction. However, the nervous and respiratory control signals can be too strong or weak in some instances. In such cases, the chemical factors play a significant role in maintaining equilibrium. The adjust­ment of respiration brings the body fluids’ carbon dioxide, oxygen and hydrogen ion concentrations to normal levels.

When a person ascends to a high altitude slowly, several compensatory mechanisms develop in the body. At higher altitudes, the partial pressure of oxygen in the arterial blood decreases due to hypoxia. It causes the stimulation of periph­eral chemoreceptors, which leads to hyperventilation. Hyper­ventilation, in turn, increases the partial pressure of oxygen in the arterial blood. The other acclimatisation responses are polycythaemia leading to a rise in RBC count due to erythro­poietin production by the kidneys under a hypoxic state. The 2,3-DPG concentration of the RBC increases at high altitude, which shifts the oxygen dissociation curve to the right, lead­ing to oxygen supply to the tissues by dissociation from haemoglobin. However, these compensatory mechanisms do not develop in persons who ascend to high altitudes at high speed, such as travelling via aircraft from sea to moun­tain leading to unconsciousness from high-altitude sickness.

7.9.6 Panting

The animal responds to an increase in core body temperature through regulatory mechanisms involving the respiratory centre, whereby the metabolic needs are balanced by an increase in respiratory frequency, which increases the dead­space ventilation, thereby increasing the evaporative heat loss accompanied by a fall in tidal volume. Panting is an impor­tant mechanism of controlling body temperature, particularly in smaller animals, whereas for larger mammalian species, sweating regulates body temperature. During panting, the alveolar ventilation remains unaffected, maintaining a con­stant partial carbon dioxide pressure in the alveolar air. Panting may occur in three patterns: (1) where the air is inhaled and exhaled through the nose; (2) air is inhaled through the nose and exhaled through both nose and mouth; and (3) where the air is inhaled and exhaled through both nose and mouth. It is to be mentioned here that maximum cooling can be achieved when the air is directed through the nose and leaves through the mouth and the minimum occurs when the air is inhaled and exhaled through the nose. When the ambient temperature is above 30 °C, (2) and (3) types of panting are observed in dogs. While air moves through the nasal cavity and mouth, the evaporative heat loss occurs mostly over the nasal mucosa and the tongue. The nasal mucosa receives a continuous supply of water from the nasal and orbital glandular secretions, which provides for this evaporative cooling by increasing the secretions with an increase in ambient temperature.

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